| Written | 2002-05 | Daniel Sinnett |
| Division of Hematology-oncology, Research Centre, Sainte-Justine Hospital, 3175 Côte Sainte-Catherine, Montreal, H3T 1C5, Québec, Canada |
| Identity |
| Alias (NCBI) | Glypican-3 (GPC3) | MXR7 | OCI-5 | GTR2-2 |
| HGNC (Hugo) | GPC3 |
| HGNC Alias symb | OCI-5 | SGBS | SGBS1 | SGB | DGSX |
| HGNC Alias name | glypican proteoglycan 3 |
| HGNC Previous name | SDYS |
| LocusID (NCBI) | 2719 |
| Atlas_Id | 156 |
| Location | Xq26.2 [Link to chromosome band Xq26] |
| Location_base_pair | Starts at 133535746 and ends at 133985594 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping GPC3.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| CD74 (5q32) / GPC3 (Xq26.2) | GPC3 (Xq26.2) / PDGFRA (4q12) | GPC4 (Xq26.2) / GPC3 (Xq26.2) | |
| HS6ST2 (Xq26.2) / GPC3 (Xq26.2) | LRPPRC (2p21) / GPC3 (Xq26.2) | NUP85 (17q25.1) / GPC3 (Xq26.2) | |
| TNKS (8p23.1) / GPC3 (Xq26.2) | TTL (2q13) / GPC3 (Xq26.2) |
| DNA/RNA |
| Description | The gene spans more than 500 kb of DNA consisting of 8 exons. |
| Transcription | 2.2kb mRNA; 1740 bp open reading frame. |
| Protein |
| Description | 580 amino acids; 65 kDa protein. GPC3 is a heparan sulfate proteoglycan (HSPG) that is attached to the cell surface via a glycosyl-phosphatidylinositol (GPI) anchor. |
| Expression | GPC3 is highly expressed in embryonal tissues such as the developing intestine and the mesoderm-derived tissues, and its expression is downregulated in most adult tissue. |
| Localisation | Attached to the membrane by a GPI anchor. |
| Function | The biochemical function of GPC3 has yet to be established. HSPG may be involved in the suppression/modulation of growth in the predominantly mesodermal tissues and organs; may play a role in the modulation of IGF-II interactions with its receptor and thereby modulate its function; can have a potential role as a regulator of growth and tumor predisposition. Therefore it is likely that GPC3 is able not only to bind more than one growth factor, but also to functionally affect the signalling of different growth factors. A role for GPC3 in the regulation of insulin-like growth (IGF) factors has been proposed. IGF-II is a growth factor that can act as a survival factor in the early stages of tumourigenesis. The co-expression of GPC3 and IGF-II has been observed in embryonal tumors as well as in mouse foetal tissues; GPC3 expression is able to induce apoptosis in a cell-specific manner, but this effect could be reversed by the addition of IGF peptides; IGFs could be needed to prevent GPC3-induced apoptosis in any cell, allowing cellular responses to other factors to take place and be mediated, enhanced or inhibited by GPC3; GPC3 mutations lead to SGBS (see below), a syndrome that shares significant similarities with the Beckwith-Wiedemann syndrome that is an overgrowth syndrome that is thought to be associated with increased expression of IGF2. |
| Homology | Belongs to the glypican family; six members, glypican-1 to 6, have been identified in mammalians; the protein core of glypicans are 20-50% identical; The glypican family is represented by at least two known members in Drosophila, dally and dally-like. |
| Mutations |
| Germinal | Most known mutations are deletions involving different exons of GPC3; missense, nonsense as well as splicing site mutations. |
| Somatic | The expression of GPC3 is altered in cancer cells. GPC3 is upregulated in hepatocellular carcinoma, in Wilm's tumor and in metastatics colorectal malignancie. With regard to tumours with neuronal phenotype, GPC3 was detected at variable levels in a neurofibrosarcoma and in most neuroblastomas, but was absent from medulloblastomas. These findings suggest that GPC3 expression is differentially regulated in the various cell lineages giving rise to pediatric tumours of the peripheral and central nervous systems. On the other hand, GPC3 is frequently silenced in mesotheliomas, in ovarian cancer cell lines and in breast cancer, often due to hypermethylation of the GPC3 promoter. |
| Implicated in |
| Note | |
| Entity | Simpson-Golabi-Behmel Syndrome (SGBS) |
| Disease | X-linked disease characterized by a wide variety of clinical manifestations, including pre- and post-natal overgrowth, tissue dysplasia, in particular of the kidneys, and cardiac anomalies; associated with a greater risk of developing embryonal cancers; caused by loss-of-function mutation in the GPC3 gene ; the abnormalities found in SGBS patients suggest that GPC3 might be involved in the regulation of growth and/or apoptosis during development. |
| To be noted |
| The ability of GPC3 to bind various growth factors or morphogens, including IGF-II, Fibroblast Growth Factor 2 as well as the tissue factor pathway inhibitor, is supported by evidence from other members of the glypican family and HSPGs in general. HSPGs of the cell surface are highly interactive macromolecules playing various roles in cell migration, proliferation, differentiation and adhesion, and participating in many developmental and pathological processes. HSPGs consist of two major families: syndecans and glypicans. Syndecans are attached to the cell membrane by a transmembrane domain while glypicans are attached through a GPI anchor. To date six members of the glypican family, glypican-1 to 6, have been identified in mammalians ; the glypican family is represented by at least two known members in Drosophila, dally and dally-like. Dally is now known to act as a co-receptor that controls signalling by morphogens and growth factors such as decapentaplegic (dpp) and wingless. Although GPC3 cannot as yet be thought of as the strict orthologue of dally, this information strengthens the notion that it may have growth factor binding and regulatory properties. |
| Bibliography |
| Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition. |
| DeBaun MR, Ess J, Saunders S |
| Molecular genetics and metabolism. 2001 ; 72 (4) : 279-286. |
| PMID 11286501 |
| Glypicans in growth control and cancer. |
| Filmus J |
| Glycobiology. 2001 ; 11 (3) : 19R-23R. |
| PMID 11320054 |
| Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine. |
| Filmus J, Church JG, Buick RN |
| Molecular and cellular biology. 1988 ; 8 (10) : 4243-4249. |
| PMID 3185547 |
| Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. |
| Hsu HC, Cheng W, Lai PL |
| Cancer research. 1997 ; 57 (22) : 5179-5184. |
| PMID 9371521 |
| Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21. |
| Hughes-Benzie RM, Hunter AG, Allanson JE, Mackenzie AE |
| American journal of medical genetics. 1992 ; 43 (1-2) : 428-435. |
| PMID 1605222 |
| dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp. |
| Jackson SM, Nakato H, Sugiura M, Jannuzi A, Oakes R, Kaluza V, Golden C, Selleck SB |
| Development (Cambridge, England). 1997 ; 124 (20) : 4113-4120. |
| PMID 9374407 |
| Dally-like protein, a new Drosophila glypican with expression overlapping with wingless. |
| Khare N, Baumgartner S |
| Mechanisms of development. 2000 ; 99 (1-2) : 199-202. |
| PMID 11091094 |
| Expression of the novel mitoxantrone resistance associated gene MXR7 in colorectal malignancies. |
| Lage H, Dietel M, Fröschle G, Reymann A |
| International journal of clinical pharmacology and therapeutics. 1998 ; 36 (1) : 58-60. |
| PMID 9476151 |
| Overgrowth syndromes and genomic imprinting: from mouse to man. |
| Li M, Squire JA, Weksberg R |
| Clinical genetics. 1998 ; 53 (3) : 165-170. |
| PMID 9630066 |
| Frequent silencing of the GPC3 gene in ovarian cancer cell lines. |
| Lin H, Huber R, Schlessinger D, Morin PJ |
| Cancer research. 1999 ; 59 (4) : 807-810. |
| PMID 10029067 |
| Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling. |
| Lin X, Perrimon N |
| Nature. 1999 ; 400 (6741) : 281-284. |
| PMID 10421372 |
| Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor. |
| Mast AE, Higuchi DA, Huang ZF, Warshawsky I, Schwartz AL, Broze GJ Jr |
| The Biochemical journal. 1997 ; 327 ( Pt 2) : 577-583. |
| PMID 9359432 |
| Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma. |
| Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC, Jhanwar SC, Mossman BT, Filmus J, Testa JR |
| Oncogene. 2000 ; 19 (3) : 410-416. |
| PMID 10656689 |
| The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patterning during postembryonic development of the nervous system in Drosophila. |
| Nakato H, Futch TA, Selleck SB |
| Development (Cambridge, England). 1995 ; 121 (11) : 3687-3702. |
| PMID 8582281 |
| Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome. |
| Neri G, Gurrieri F, Zanni G, Lin A |
| American journal of medical genetics. 1998 ; 79 (4) : 279-283. |
| PMID 9781908 |
| Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome. |
| Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M, Cao A, Schlessinger D, Forabosco A |
| Developmental dynamics : an official publication of the American Association of Anatomists. 1998 ; 213 (4) : 431-439. |
| PMID 9853964 |
| Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. |
| Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D |
| Nature genetics. 1996 ; 12 (3) : 241-247. |
| PMID 8589713 |
| Expression of glypican 3 (GPC3) in embryonal tumors. |
| Saikali Z, Sinnett D |
| International journal of cancer. Journal international du cancer. 2000 ; 89 (5) : 418-422. |
| PMID 11008203 |
| OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. |
| Song HH, Shi W, Filmus J |
| The Journal of biological chemistry. 1997 ; 272 (12) : 7574-7577. |
| PMID 9065409 |
| The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila. |
| Tsuda M, Kamimura K, Nakato H, Archer M, Staatz W, Fox B, Humphrey M, Olson S, Futch T, Kaluza V, Siegfried E, Stam L, Selleck SB |
| Nature. 1999 ; 400 (6741) : 276-280. |
| PMID 10421371 |
| Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions. |
| Tumova S, Woods A, Couchman JR |
| The international journal of biochemistry & cell biology. 2000 ; 32 (3) : 269-288. |
| PMID 10716625 |
| Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. |
| Veugelers M, Cat BD, Muyldermans SY, Reekmans G, Delande N, Frints S, Legius E, Fryns JP, Schrander-Stumpel C, Weidle B, Magdalena N, David G |
| Human molecular genetics. 2000 ; 9 (9) : 1321-1328. |
| PMID 10814714 |
| Glypican-3 expression is silenced in human breast cancer. |
| Xiang YY, Ladeda V, Filmus J |
| Oncogene. 2001 ; 20 (50) : 7408-7412. |
| PMID 11704870 |
| Citation |
| This paper should be referenced as such : |
| Sinnett, D |
| Glypican-3 (GPC3) |
| Atlas Genet Cytogenet Oncol Haematol. 2002;6(3):206-208. |
| Free journal version : [ pdf ] [ DOI ] |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 4 ] |
|
Liver: Fibrolamellar carcinoma
GPC4/GPC3 (Xq26) t(X;17)(q26;q25) NUP85/GPC3 Kidney: Nephroblastoma (Wilms tumor) |
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Simpson-Golabi-Behmel syndrome |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jan 1 18:52:45 CET 2021 |
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